Featured Research

from universities, journals, and other organizations

DNA of 50 breast cancer patients decoded

Date:

April 3, 2011

Source:

Washington University School of Medicine

Summary:

In the single largest cancer genomics investigation reported to date, scientists have sequenced the whole genomes of tumors from 50 breast cancer patients and compared them to the matched DNA of the same patients' healthy cells. They uncovered incredible complexity in the cancer genomes, but also got a glimpse of new routes toward personalized medicine.

In the single largest cancer genomics investigation reported to date, scientists have sequenced the whole genomes of tumors from 50 breast cancer patients and compared them to the matched DNA of the same patients' healthy cells. This comparison allowed researchers to find mutations that only occurred in the cancer cells.

Related Articles

They uncovered incredible complexity in the cancer genomes, but also got a glimpse of new routes toward personalized medicine. The work was presented at the American Association for Cancer Research 102nd Annual Meeting 2011.

In all, the tumors had more than 1,700 mutations, most of which were unique to the individual, says Matthew J. Ellis, MD, PhD, professor of medicine at Washington University School of Medicine in St. Louis and a lead investigator on the project.

To undertake the massive task, Washington University oncologists and pathologists at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine collaborated with the university's Genome Institute to sequence more than 10 trillion chemical bases of DNA -- repeating the sequencing of each patient's tumor and healthy DNA about 30 times to ensure accurate data.

"The computing facilities required to analyze this amount of data are similar in scale to those of the Large Hadron Collider, used to understand the workings of sub-atomic particles," Ellis says.

The DNA samples came from patients enrolled in a clinical trial that Ellis is leading for the American College of Surgeons Oncology Group. All patients in the trial had what is called estrogen-receptor-positive breast cancer. These cancer cells have receptors that bind to the hormone estrogen and help the tumors grow.

To slow tumor growth and make the tumors easier to remove, patients received estrogen-lowering drugs before surgery. But, for unknown reasons, this treatment does not always work. Twenty-four of the 50 tumor samples came from patients whose tumors were resistant to this treatment, and 26 came from patients whose tumors responded. Comparing the two groups might help explain why some estrogen-receptor-positive breast cancer patients do well with estrogen-lowering drugs and others poorly.

Confirming previous work, Ellis and colleagues found that two mutations were relatively common in many of the patients' cancers. One called PIK3CA is present in about 40 percent of breast cancers that express receptors for estrogen. Another called TP53 is present in about 20 percent.

Adding to this short list of common mutations, Ellis and colleagues found a third, MAP3K1, that controls programmed cell death and is disabled in about 10 percent of estrogen-receptor-positive breast cancers. The mutated gene allows cells that should die to continue living. Only two other genes, ATR and MYST3, harbored mutations that recurred at a similar frequency as MAP3K1 and were statistically significant.

"To get through this experiment and find only three additional gene mutations at the 10 percent recurrence level was a bit of a shock," Ellis says.

In addition, they found 21 genes that were also significantly mutated, but at much lower rates -- never appearing in more than two or three patients. Despite the relative rarity of these mutations, Ellis stresses their importance.

"Breast cancer is so common that mutations that recur at a 5 percent frequency level still involve many thousands of women," he says.

Ellis points out that some mutations that are rare in breast cancer may be common in other cancers and already have drugs designed to treat them.

"You may find the rare breast cancer patient whose tumor has a mutation that's more commonly found in leukemia, for example. So you might give that breast cancer patient a leukemia drug," Ellis says.

But such treatment is only possible when the cancer's genetics are known in advance. Ideally, Ellis says, the goal is to design treatments by sequencing the tumor genome when the cancer is first diagnosed.

"We get good therapeutic ideas from the genomic information," he says. "The near-term goal is to use information on whole genome sequencing to guide a personalized approach to the patient's treatment."

This work builds on previous collaborations between Washington University oncologists and the Genome Institute. In a study published last year in Nature, they reported the complete tumor and normal DNA sequences of a woman with "triple-negative" breast cancer, a particularly aggressive type that is difficult to treat and more common in younger women and African-Americans.

While many mutations are rare or even unique to one patient, Ellis says quite a few can be classified on the basis of common biological effects and therefore could be considered together for a particular therapeutic approach.

Ellis looks to future work to help make sense of breast cancer's complexity. But these highly detailed genome maps are an important first step.

"At least we're reaching the limits of the complexity of the problem," he says. "It's not like looking into a telescope and wondering how far the universe goes. Ultimately, the universe of breast cancer is restricted by the size of the human genome."

Reference: Ellis et al. Breast cancer genome. Presented April 2, 2011, at the 102nd Annual Meeting of the American Association for Cancer Research in Orlando, Fla.

This work was supported by grants from the National Human Genome Research Institute, the Breast Cancer Research Foundation, the National Cancer Institute, Susan G. Komen for the Cure and Washington University School of Medicine.

Featured Research

Mar. 31, 2015  Researchers have illuminated an important distinction between mice and humans: how human livers heal. The difference centers on a protein called PPAR alpha which activates liver ... full story

Mar. 31, 2015  Researchers have recorded the first direct observations of the micro-scale mechanisms behind the ability of skin to resist tearing. The results could be applied to the improvement of artificial skin, ... full story

Mar. 31, 2015  Fewer than half of the physicians trained in the United States in 2013 received formal education or training on the subject of exercise, according to new research. "There are immense medical benefits ... full story

Mar. 31, 2015  Memory and as well as connections between brain cells were restored in mice with a model of Alzheimer's given an experimental cancer drug, researchers report. "With this treatment, cells under ... full story

Mar. 31, 2015  Increasing state alcohol taxes could prevent thousands of deaths a year from car crashes, say researchers, who found alcohol-related motor vehicle crashes decreased after taxes on beer, wine and ... full story

Mar. 31, 2015  Alcoholism takes a toll on every aspect of a person's life, including skin problems. Now, a new research report helps explain why this happens and what might be done to address it. "The clinical ... full story

Mar. 31, 2015  A new population of 'memory' immune cells has been discovered by scientists, throwing light on what the body does when it sees a microbe for the second time. This insight, and others like it, will ... full story

Mar. 31, 2015  Coronary heart disease and stroke, two of the leading causes of death in the United States, are diseases associated with heightened platelet reactivity. A new study in humans suggests an underlying ... full story

Mar. 31, 2015  A new study had researchers seeking answers to why the therapeutic benefit afforded by SSRIs was so limited in children and teenagers. If researchers can uncover the biological mechanisms preventing ... full story

Featured Videos

Solitair Device Aims to Takes Guesswork out of Sun Safety

Reuters - Innovations Video Online (Mar. 31, 2015)  The Solitair device aims to take the confusion out of how much sunlight we should expose our skin to. Small enough to be worn as a tie or hair clip, it monitors the user&apos;s sun exposure by taking into account their skin pigment, location and schedule. Matthew Stock reports.
Video provided by Reuters

Soda, Salt and Sugar: The Next Generation of Taxes

Washington Post (Mar. 30, 2015)  Denisa Livingston, a health advocate for the Dinι Community Advocacy Alliance, and the Post&apos;s Abby Phillip discuss efforts around the country to make unhealthy food choices hurt your wallet as much as your waistline.
Video provided by Washington Post

S. Leone in New Anti-Ebola Lockdown

AFP (Mar. 28, 2015)  Sierra Leone imposed a three-day nationwide lockdown Friday for the second time in six months in a bid to prevent a resurgence of the deadly Ebola virus. Duration: 01:17
Video provided by AFP

Related Stories

Jan. 7, 2014  Researchers have examined whether a specific epigenetic modification (more specifically, methylation of the DNA) can be associated to breast cancer family history in unaffected women from high-risk ... full story

Dec. 12, 2013  New research examined how changes in the genetic composition of breast cancer tumors after brief exposure to either biologic therapy or chemotherapy can predict future clinical outcomes in ... full story

Mar. 3, 2011  Using recent advances in genomics, researchers have uncovered a genetic pathway that affects the development of breast cancer, work that could help predict which patients are at risk of relapse for ... full story

Oct. 18, 2010  Breast cancers can be divided into different subtypes. Patients with breast tumors that lack expression of the protein ER (ER-negative breast tumors) have a worse outlook than those with ER-positive ... full story

ScienceDaily features breaking news and videos about the latest discoveries in health, technology, the environment, and more -- from major news services and leading universities, scientific journals, and research organizations.